Maternal infections in pregnancy and the risk of sudden unexpected infant death in the offspring in the U.S., 2011–2015

Background Infection is thought to play a part in some infant deaths. Maternal infection in pregnancy has focused on chlamydia with some reports suggesting an association with sudden unexpected infant death (SUID). Objectives We hypothesized that maternal infections in pregnancy are associated with subsequent SUID in their offspring. Setting All births in the United States, 2011–2015 Data source Centers for Disease Control and Prevention (CDC) Birth Cohort Linked Birth-Infant Death Data Files. Study design Cohort study, although the data were analysed as a case control study. Cases were infants that died from SUID. Controls were randomly sampled infants that survived their first year of life; approximately 10 controls per SUID case. Exposures Chlamydia, gonorrhea and hepatitis C. Results There were 19,849,690 live births in the U.S. for the period 2011–2015. There were 37,143 infant deaths of which 17,398 were classified as SUID cases (a rate of 0.86/1000 live births). The proportion of the control mothers with chlamydia was 1.7%, gonorrhea 0.2% and hepatitis C was 0.3%. Chlamydia was present in 3.8% of mothers whose infants subsequently died of SUID compared with 1.7% of controls (unadjusted OR = 2.35, 95% CI = 2.15, 2.56; adjusted OR = 1.08, 95% CI = 0.98, 1.19). Gonorrhea was present in 0.7% of mothers of SUID cases compared with 0.2% of mothers of controls (OR = 3.09, (2.50, 3.79); aOR = 1.20(0.95, 1.49)) and hepatitis C was present in 1.3% of mothers of SUID cases compared with 0.3% of mothers of controls (OR = 4.69 (3.97, 5.52): aOR = 1.80 (1.50, 2.15)). Conclusions The marked attenuation of SUID risk after adjustment for a wide variety of socioeconomic and demographic factors suggests the small increase in the risk of SUID of the offspring of mothers with infection with hepatitis C in pregnancy is due to residual confounding.


Introduction
In the United States (U.S.), sudden unexpected infant death (SUID) is a term that encompasses three separate causes of infant death as defined in the International Classification of Diseases, 10 th Revision (ICD-10): sudden infant death syndrome (SIDS; R95), deaths from other illdefined or unknown causes (R99), and accidental suffocation and strangulation in bed (W75). Approximately 3,500 infant deaths are classified as SUID cases annually in the U.S. [1].
As early as the 1960's, researchers have suspected a role of infections in sudden infant death [2]. This association is consistent with the seasonality of SUID, with a greater prevalence in the winter [3], and the fact that the age of death peaks around 3 months, when infants are losing maternal immunity and their own immune system is immature [4].
Studies that have specifically investigated a link between sudden infant death and sexually transmitted infections have overwhelmingly focused on chlamydia. Chlamydia trachomatis is the most common bacterial pathogen of sexually transmitted infections in women in the U.S. with a prevalence in pregnant women ranging from 2-20% depending on the risk factors for the population in a given study [5]. Transmission of the infection can pass to the newborn from an infected cervix during birth. A published abstract from 1981 found significantly higher seropositivity for Chlamydia trachomatis in SIDS infants compared to controls [6]. Maternal seropositivity is associated with stillbirths, preterm delivery, premature rupture of the membranes, and low birthweight [7][8][9][10]. Another study found chlamydia inclusions in lung sections in 19% of SIDS cases compared with 3% of infants with a known cause of death [11].
The relationship between SUID and maternal sexually transmitted diseases and other infections is likely understudied because, individually, each is a rare occurrence, so it takes a very large dataset to have the necessary statistical power. Here we used the Centers for Disease Control and Prevention (CDC) Birth Cohort Linked Birth/Infant Death Data Set that includes every birth and death in the United States to study the association between SUID and various maternal infections in pregnancy, including chlamydia, gonorrhea and hepatitis C. We hypothesized that these maternal infections in pregnancy are associated with subsequent SUID in their offspring.

Study design
The study design is a population-based cohort study of all births and their mothers occurring in the U.S. from 2011 to 2015. Due to the very large sample size, infants that survived their first year of life (referred to as controls) were randomly sampled so there were approximately 10 controls for each SUID. The data were analysed as a case control study. Reporting of this study follows the STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) guidelines [12].

Data source
The cohort data were sourced from the publicly available Centers for Disease Control and Prevention (CDC) Birth Cohort Linked Birth-Infant Death Data Files [13]. Each contained several hundreds of features detailing various aspects of the mother's and father's background, the pregnancy and the birth of the infant. Additionally, the data includes details concerning the death of any infant in the first year of life.

Exposure variable
The following maternal infections in pregnancy were examined: chlamydia, hepatitis C, hepatitis B, gonorrhea and syphilis. These are reported as Yes, No, Unknown or not stated.

Outcome-SUID
Infants who died under 1 year of age and whose cause of death were certified as due to any one of the following International Classification of Diseases, 10th Revision (ICD10) codes: R95 (sudden infant death syndrome, SIDS), R99 (other ill-defined and unspecified cause of mortality) or W75 (accidental suffocation and strangulation in bed). Deaths that occurred in infant's first 7 days of life were excluded as the epidemiology is different from those dying between 7 and 365 days of life [14].

Covariates
The analysis adjusted for the following variables, which are known to be associated with SUDI [15,16] and were in the linked dataset: mother's age, mother's education, mother's race/Hispanic origin, marital status, smoking before pregnancy, smoking during pregnancy, delivery method, gestational age, sex of infant, father's age, father's race/Hispanic origin, live birth order, month prenatal care began and birthweight. The definition, origin and categorisation of these variables were:

Statistical analysis
Relative risks were estimated by calculation of odds ratios (OR). The univariable and multivariable ORs were obtained from unconditional logistic regression modelling as were their confidence intervals (CI). Population attributable risks (PAR) were calculated to estimate the unadjusted proportion of deaths explained by exposure to maternal infections [17].

Results
There

Controls
Of the 19,732,933 infants born in the study period that survived to their first birthday a sample of 166,985 infants were randomly selected so that there was approximately 10 controls for each SUID case) This sample was used in this analysis. Table 1 describes the characteristics of the study population (cases and controls). The proportion of the controls with chlamydia was 1.7%, gonorrhea 0.2% and hepatitis C was 0.3%. Due to small numbers, syphilis and hepatitis B were not considered further. Table 2 shows the characteristics of the exposures (chlamydia, gonorrhea, and hepatitis C).
The population attributable fractions for chlamydia, gonorrhea and hepatitis C are 2.2%, 0.5% and 1.0% respectively.

Discussion
This study found that maternal infection with chlamydia, gonorrhea and hepatis C during pregnancy was associated with an increased risk of SUID in the offspring. After adjustment for a wide range of sociodemographic and other risk factors for SUID, the magnitude of the risk was attenuated, but remained statistically significant for hepatitis C.  Some infections, for example syphilis and HIV (human immunodeficiency virus), can pass across the placenta and infect the fetus in utero. Other sexually transmitted diseases, like gonorrhea, chlamydia, hepatitis B, and genital herpes, can pass from the mother to the baby as the baby passes through the genital tract. Our analysis adjusted for mode of delivery. A meta-analysis found that cesarean delivery did not decrease the risk of perinatal transmission of hepatitis C virus from positive mothers [18]. One possible explanation is that vaginal birth does not simply increase the risk of transmitted infections, but it may also convey increased protection against infections, for example through the gut microbiome. There is increasing evidence that infants born by Cesarean delivery lack bacteria that are important for the stabilization of the gut microbiota [19]. Clearly, our study cannot provide insights into causal relationships. The most likely explanation for our findings is residual confounding.
This study has shown that these maternal infections in pregnancy are associated with young maternal age, less maternal education, unmarried, Hispanic and Black race, and maternal smoking both before and during pregnancy. All these factors are also known risk factors for SUID. We speculate that this may account for previous findings of a higher seropositivity for chlamydia 6 and greater frequency of chlamydia inclusions in the lungs of SUID cases [11].
Limitations of this study must be considered. The prevalence of these infections is at the lower limits of that reported from other studies, which may reflect those other studies were conducted for more selected and higher risk populations. In contrast this study was unbiased as it considered the entire population of births in the U.S. over 5 years. The infections  identified within our study may reflect not only identification of the infections but also that they have been treated. The dataset does not record information on whether they have been treated. A further limitation is the missing data for the covariates, but since the loss was similar in both cases and controls for both the exposures (9.0% and 8,5% respectively) and covariates, with the exception of father's age and origin, it is unlikely to have affected the results. Father's  age was unknown for 30.3% of cases and 12.5% of controls and father's origin was unknown for 35.6% and 18.4% respectively. This reflects that SUID is more common for parents that are unmarried and disadvantaged. This study has examined chlamydia, gonorrhea and hepatitis C. There were insufficient numbers to examine syphilis and hepatitis B. Other infections, such as bacterial vaginosis and human immunodeficiency virus (HIV), are not reported in the publicly available CDC Birth Cohort Linked Birth-Infant Death Data Files. Bacterial vaginosis may be a cause of SUID as it causes preterm birth and low birthweight [20], which are established risk factors for SUID. This suggests maternal infection, especially relating to the genital tract in pregnancy should not be entirely discounted.

Conclusions
We conclude that even if there is a causal link, the number of cases that could be attributed to these infections is small. This does not negate the fact that these infections in pregnancy are important and cause a wide range of health problems to the mother, fetus, and infant. In conclusion, even though we argue that SUID is not a direct consequence of these infections, paying a holistic assessment of the mother's health conditions and being extra vigilant on an infant during early months of birth may be beneficial.